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The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine 总被引:13,自引:0,他引:13
Shimma N Umeda I Arasaki M Murasaki C Masubuchi K Kohchi Y Miwa M Ura M Sawada N Tahara H Kuruma I Horii I Ishitsuka H 《Bioorganic & medicinal chemistry》2000,8(7):1697-1706
To identify an orally available fluoropyrimidine having efficacy and safety profiles greatly improved over those of parenteral 5-fluorouracil (5-FU: 1), we designed a 5-FU prodrug that would pass intact through the intestinal mucisa and be sequentially converted to 5-FU by enzymes that are highly expressed in the human liver and then in tumors. Among various N4-substituted 5'-deoxy-5-fluorocytidine derivatives, a series of N4-alkoxycarbonyl derivatives were hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR: 8) specifically by carboxylesterase, which exists preferentially in the liver in humans and monkeys. Particularly, derivatives having an N4-alkoxylcarbonyl moiety with a C4-C6 alkyl chain were the most susceptible to the human carboxylesterase. Those were then converted to 5'-deoxy-5-fluorouridine (5'-DFUR: 4) by cytidine deaminase highly expressed in the liver and solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumors. When administered orally to monkeys, a derivative having the N4-alkoxylcarbonyl moiety with a C5 alkyl chain (capecitabine: 6) The highest AUC and Cmax for plasma 5'-DFUR. In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys. 相似文献
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Yoshinori Funama Katsuyuki Taguchi Daisuke Utsunomiya Seitaro Oda Hiroo Murasaki Yasuyuki Yamashita Kazuo Awai 《Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB)》2012,28(1):76-82
PurposeThe purpose of our study was to acquire dose profiles at critical organs of lung and breast regions using optically stimulated luminescence (OSL) dosimeters; assess the actual radiation dose delivered at retrospective and prospective computed tomography coronary angiography (CTCA).Materials and methodsUsing a chest CT phantom we applied a prospectively-gated step-and-shoot- and a retrospectively-gated helical mode on a 64-detector row CT scanner. Retrospective scan mode was used with and without electrocardiogram (ECG) based tube current modulation. OSL dosimeters were used to measure dose profiles. In the both scan modes we acquired dose profiles and determined the mean and maximum dose in left lung and in left breast regions.ResultsIn prospective mode, the mean dose was 21.53 mGy in left lung- and 23.59 mGy in left breast region. With respect to the retrospective mode, the mean dose with tube current modulation was 38.63 mGy for left lung- and 46.02 mGy for left breast region, i.e. 0.56 and 0.55 times lower than the mean dose without modulation.ConclusionThe OSL dosimeter is useful for measurement of the actual radiation dose along z-axis at lung and breast regions in the prospective and the retrospective CTCA. 相似文献
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A new species of liparid fish Careproctus surugaensis is described from a single specimen collected between 1,450 and 1,570 m depth on the northern part of Suruga Trough, Suruga Bay, Japan. It can be distinguished from all currently recognized congeners by the following combination of characters: 50 total vertebrae, 47 dorsal-fin rays, 39 anal-fin rays, 32 pectoral-fin rays, 10 principal caudal-fin rays, pectoral proximal radials 4 (first to third with notches); trilobate teeth on both jaws, gill slit 7.1 % SL, extending in front of 7th pectoral fin ray base; maximum body depth 19.1 % SL, disk length 7.9 % SL, anus midway between posterior margin of pelvic disk and anal-fin origin; body and fins light orange except blackish peritoneum. 相似文献
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Jun Ohwada Sawako Ozawa Masami Kohchi Hiroshi Fukuda Chikako Murasaki Hitomi Suda Takeshi Murata Satoshi Niizuma Masao Tsukazaki Kazutomo Ori Kiyoshi Yoshinari Yoshiko Itezono Mika Endo Masako Ura Hiromi Tanimura Yoko Miyazaki Akira Kawashima Shunsuke Nagao Eitarou Namba Koutarou Ogawa Nobuo Shimma 《Bioorganic & medicinal chemistry letters》2009,19(10):2772-2776
CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10 mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1 min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models. 相似文献
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A green cell suspension culture was established from callus tissue obtained from a moss,Atrichum undulatum. This suspension culture was subcultured every ten days in Murashige and Skoog's liquid medium (MS) containing 10?6 M 2, 4-D and 4% glucose. The suspended cells grew vigorously with the passage of subculture, maintaining small clusters made up of a few cells. In this suspension culture, round spore-like cells released from the cell clusters were found. The yield of protoplasts from the suspension culture was significantly higher than that of the conventional method using moss protonemata developed directly from spores. 相似文献
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Satoshi Niizuma Masao Tsukazaki Hitomi Suda Takeshi Murata Jun Ohwada Sawako Ozawa Hiroshi Fukuda Chikako Murasaki Masami Kohchi Kenji Morikami Kiyoshi Yoshinari Mika Endo Masako Ura Hiromi Tanimura Yoko Miyazaki Tsuyoshi Takasuka Akira Kawashima Eitaro Nanba Kounosuke Nakano Kotaro Ogawa Nobuo Shimma 《Bioorganic & medicinal chemistry letters》2009,19(7):2018-2021
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines. 相似文献
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Uezono Y Kaibara M Murasaki O Taniyama K 《American journal of physiology. Cell physiology》2004,287(4):C885-C894
We studied the functions of -subunits of Gi/o protein using the Xenopus oocyte expression system. Isoproterenol (ISO) elicited cAMP production and slowly activating Cl currents in oocytes expressing 2-adrenoceptor and the protein kinase A-dependent Cl channel encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene. 5-Hydroxytryptamine (5-HT), [D-Ala2, D-Leu5]-enkephalin (DADLE), and baclofen enhanced ISO-induced cAMP levels and CFTR currents in oocytes expressing 2-adrenoceptor-CFTR and 5-HT1A receptor (5-HT1AR), -opioid receptor, or GABAB receptor, respectively. 5-HT also enhanced pituitary adenylate cyclase activating peptide (PACAP) 38-induced cAMP levels and CFTR currents in oocytes expressing PACAP receptor, CFTR and 5-HT1AR. The 5-HT-induced enhancement of Gs-coupled receptor-mediated currents was abrogated by pretreatment with pertussis toxin (PTX) and coexpression of G transducin (Gt). The 5-HT-induced enhancement was further augmented by coexpression of the G-activated form of adenylate cyclase (AC) type II but not AC type III. Thus -subunits of Gi/o protein contribute to the enhancement of Gs-coupled receptor-mediated responses. 5-HT and DADLE did not elicit any currents in oocytes expressing 5-HT1AR or -opioid receptor alone. They elicited Ca2+-activated Cl currents in oocytes coexpressing these receptors with the G-activated form of phospholipase C (PLC)-2 but not with PLC-1. These currents were inhibited by pretreatment with PTX and coexpression of Gt, suggesting that -subunits of Gi/o protein activate PLC-2 and then cause intracellular Ca2+ mobilization. Our results indicate that -subunits of Gi/o protein participate in diverse intracellular signals, enhancement of Gs-coupled receptor-mediated responses, and intracellular Ca2+ mobilization. G protein-coupled receptor; cystic fibrosis transmembrane conductance regulator gene; cross talk; electrophysiology 相似文献
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Ichthyological Research - The new snailfish Paraliparis variabilidens is described from a single specimen collected between 1,462 and 1,562 m depth in the northern part of the Suruga... 相似文献